© 2001 Nature Publishing Group http://immunol.nature.com REVIEW Plasma cells: finding new light at the end of B cell development Kathryn L. Calame Plasma cells are cellular factories devoted entire- Upon plasma cell differentiation, there is a marked increase in ly to the manufacture and export of a single prod- steady-state amounts of Ig heavy and light chain mRNA and, when 2 uct: soluble immunoglobulin (Ig). As the final required for IgM and IgA secretion, J chain mRNA . Whether the increase in Ig mRNA is due to increased transcription, increased mediators of a humoral response, plasma cells mRNA stability or, as seems likely, both mechanisms, remains con- play a critical role in adaptive immunity.Although troversial2. There is also an increase in secreted versus membrane intense effort has been devoted to studying the forms of heavy chain mRNA, as determined by differential use of poly(A) sites that may involve the availability of one component of regulation and requirements for early B cell the polyadenylation machinery, cleavage-stimulation factor Cst-643. development, little information has been avail- To accommodate translation and secretion of the abundant Ig able on plasma cells. However, more recent mRNAs, plasma cells have an increased cytoplasmic to nuclear ratio work—including studies on genetically altered and prominent amounts of rough endoplasmic reticulum and secreto- ry vacuoles. mice and data from microarray analyses—has Numerous B cell–specific surface proteins are down-regulated begun to identify the regulatory cascades that upon plasma cell differentiation, including major histocompatibility initiate and maintain the plasma cell phenotype. complex (MHC) class II, B220, CD19, CD21 and CD22. MHC class This review will summarize our current under- II, which is required for antigen presentation to T cells, is absent due to lack of class II transactivator (CIITA), a coactivator required for standing of the molecules that regulate commit- transcription of MHC class II, invariant chain and HLA-DM4. The ment to a plasma cell fate and those that medi- proteoglycan syndecan-1, which recognizes extracellular matrix and ate plasma cell function. growth factors, is induced on antibody-secreting B cells and is often used as a marker of plasma cells5. Among integrin family proteins, © http://immunol.nature.com Group 2001 Nature Publishing which mediate cell-matrix and cell-cell adhesion functions, VLA-4 Plasma cells are interesting for several reasons. On a basic level, they (very late antigen 4) is most predominant on plasma cells. Perhaps show the general mechanisms involved in the commitment of somat- most important for differential homing of plasma cells, the ic cells to a terminally differentiated, post-mitotic state. As final chemokine receptors CXCR5 and CCR7 are decreased, which mediators of the humoral immune response, they provide insights reduces responsiveness to the B and T cell zone chemokines into the regulation of humoral immunity that may be helpful for vac- CXCL13, CCL19 and CCL216. In contrast, expression of CXCR4, cine development. They may also aid our understanding of certain which recognizes CXCL12 present in splenic red pulp, lymph node human diseases. For example, information about normal plasma cells medullary cords and in bone marrow, remains high6. These changes may help us understand human multiple myeloma, a disease that mediate movement of plasma cells from the follicles to other loca- involves malignant plasma cells. In addition, soluble antibodies or tions, including the bone marrow. immune complexes are pathological in many autoimmune diseases, Several transcription factors required for earlier steps in B cell devel- including myasthenia gravis, Grave’s disease, lupus erythematosus opment are decreased or absent in plasma cells. These include B cell and rheumatoid arthritis. Therefore, knowledge of plasma cell biolo- lineage–specific activator (BSAP), encoded by PAX5, which is required gy may eventually provide a rational basis for designing treatments for commitment to the B cell lineage7 and for B cell lymphopoeisis in for these diseases. bone marrow and spleen8,9. CIITA is also decreased in plasma cells4. Other transcription factors expressed at earlier stages in B cell devel- Characteristics of plasma cells opment, such as early B cell factor (EBF), A-Myb and BCL-6 are also Because they are terminally differentiated, end-stage cells, plasma decreased in plasma cells. However, a few transcription factors do cells do not divide. However, “plasmablasts” in extrafollicular increase in plasma cells. B lymphocyte–induced maturation protein 1 regions or exiting germinal centers (GCs) do undergo cell division (Blimp-1) is induced upon plasma cell differentiation10 and expressed just before they become plasma cells1. The lifespan of nondividing in vivo in plasma cells and a subset of GC B cells with a partial plasma plasma cells varies from a few days to many months and, as detailed cell phenotype11. Interferon-regulatory factor 4 (IRF4), which associ- below, this appears to be determined in part by their developmental ates with the Ets family protein PU.112, is also highly expressed in the history and homing capacity as well as by the finite capacity of the Blimp-1+ subset of GC B cells and in plasma cells13. X box–binding spleen to support them1. Other characteristics of plasma cells are sum- protein 1 (XBP-1), although ubiquitously expressed, is induced upon marized below (Fig. 1). activation of B cells and increased in plasma cells14. Departments of Microbiology and Biochemistry & Molecular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Correspondence should be addressed to K. L. C. ([email protected]). http://immunol.nature.com • december 2001 • volume 2 no 12 • nature immunology 1103 © 2001 Nature Publishing Group http://immunol.nature.com REVIEW Commitment to a plasma cell fate the other hand, xid and Btk–/– mice, which show compromised BCR Naïve B cell immigrants from the bone marrow mature in a variety of signaling, have MZ B cells but reduced survival of follicular B cells27. B cell compartments. Outside the bone marrow, spleen is a major site However, alternative explanations are possible. For example, for maturation of conventional B2 cells, whereas B1 cells mature pri- decreased MZ B cells in Aiolos–/– mice could result from enhanced marily in peritoneal and pleural cavities15. In the spleen, most lym- negative selection by self-antigen. phocytes are located in white pulp nodules that are interspersed in the Tumor necrosis factor (TNF) family ligands and TNF receptors red pulp matrix16. In each white pulp nodule, blood is supplied from (TNFRs) play critical roles in determining splenic architecture and B a central arteriole surrounded by a periarteriolar sheath (PALS). T cell development16. Lymphotoxins are necessary for the establishment cells are found primarily in the PALS, whereas most B cells cluster of splenic T cell and B cell zones and TNF is involved in the forma- around follicular dendritic cells in follicles adjacent to the PALS. A tion of marginal sinuses and GCs16. In addition, two ligands—B lym- marginal zone (MZ)—which contains specialized dendritic cells and phocyte stimulator (BLyS) and APRIL (a proliferation-inducing lig- macrophages, memory and naïve B cells—surrounds the outside of and)—and three receptors—TACI (transmembrane activator and each nodule and acts as an antigen-filtering and scavenging area. CAML interactor) and BCMA (B cell maturation antigen), which rec- When naïve B cells leave the bone marrow and enter the spleen, a ognize both, and BAFF-R (B cell–activating factor receptor), which maturation process involving both positive and negative selection recognizes BLyS28—have important roles in the development of ensues and most cells die in the outer PALS. Of the surviving B cells, mature follicular and GC B cells and in Ig production29. BlyS is the majority pass through the T cell zone and enter primary follicles required for maturation of follicular B cells and TACI–/– mice have ele- where they continue to mature into naïve follicular B cells vated B cells but lack T cell–independent type 2 B cell responses30. (IgMintIgDhiCD21intCD23hi)17. A smaller fraction are found in the MZ Further studies on TNF-TNFR proteins are likely to identify addition- as naïve MZ B cells (IgMhiIgDloCD21hiCD23lo)18. Follicular B cells al roles for them in B lymphoiesis and refine our understanding of how recirculate to bone marrow and lymph nodes but MZ B cells do not they affect humoral immunity and plasmacytic differentiation. recirculate. Antigen, either in soluble form A later response to antigen occurs when or associated with dendritic cells, activates follicular B cells are recruited by T naïve B cells in various B cell compart- cell–dependent antigens into GCs in spleen ments and, ultimately, leads to terminal and lymph nodes. It is also possible, but not plasmacytic differentiation. However, plas- yet established, that some MZ or B1 cells macytic differentiation occurs at different may enter follicles and mature in GCs. The times and in different locations during an GC reaction has been intensively studied31, immune response (Fig. 2). but will not be described in detail here. MZ and B1 cells respond most rapidly to Iterative cycles of proliferation, somatic antigen, giving rise to the first wave of plas- hypermutation and apoptosis in the GC © http://immunol.nature.com Group 2001 Nature Publishing ma cells and the earliest antibody response result in the selection of B cells that make to antigen19. B1 cells are a self-renewing an antibody with high affinity for cognate Figure 1. Plasma cell. Two characteristic surface mole- subset with a restricted repertoire that pro- cules, Syndecan-1 and CXCR4, three key transcription fac- antigen. In addition, isotype switching vides a response to common bacterial anti- tors, Blimp-1, IRF4 and XBP-1, and increased endoplasmic occurs during the GC reaction. The GC gens and plays a role in autoimmunity.